Recently the identification of mutations in several genes involved in the onset of obesity in rodents have been identified. Of particular interest are mutations discovered in the peptide hormone, leptin, which is a component of a novel signal transduction pathway that regulates body weight (Zhang et al. 1994, Nature 372:425-432; Chen et al. 1996, Cell 84:491-495). Leptin was initially discovered by the positional cloning of the obesity gene, ob, in mice. Two different ob alleles have been identified: one mutation causes the premature termination of the leptin peptide resulting in a truncated protein, and the other mutation changes the transcriptional activity of the obesity (ob) gene, resulting in a reduced amount of circulating leptin.
There is a correlation between a decrease in the levels of biologically active leptin and the overt obese phenotype observed in ob/ob mice. Recombinant leptin has been shown to induce weight loss in the ob/ob mouse but not in the diabetic phenotype db/db mouse (Campfield et al. 1995, Science 269: 546-549; Halaas et al. 1995, Science 269: 543-546; Pellymounter et al. 1995, Science 269:540-543; Rentsch et al. 1995, Biochem. Biophys. Res. Comm. 214:131-136; and Weigle et al. 1995, J. Clin. Invest. 96:2065-2070).
Although the synthesis of leptin occurs in the adipocyte, its ability to decrease food intake and increase metabolic rate appears to be mediated centrally by the hypothalamus. Injection of recombinant leptin into the third ventricle of the brain elicits a similar response as peripheral administration of leptin. Furthermore, the recent cloning of the human receptor for the leptin, the ob-receptor (OB-R), reveals that it is transcribed in the hypothalamus (Tartaglia et al. 1995, Cell 83:1263-1271; Stephens et al. 1995, Nature 377: 530-532). In addition, a mutation that results in premature termination of the long-form of the mouse OB-R, which is preferentially expressed in the hypothalamus, appears to be responsible for the obese phenotype of the db/db mouse (Lee et al. 1996, Nature 379:632-635; Chua et al. 1996, Science 271:994-996; and Chen et al. 1996, Cell 84:491-495).
The fa mutation is a recessive allele that arose spontaneously in the 13M rat strain and was first reported in 1961 (Zucker et al. 1961, J. Heredity 52: 275-278. The onset of obesity in the fa/fa Zucker rat is at 5-7 weeks of age and progresses with age. The mature fatty rat is approximately twice the weight of lean litter mates and over 40% of its body weight is adipose tissue (Zucker et al. 1962, Proc. Soc. Exp. Biol. Med. 110:165-171; Zucker et al. 1963, J. Nutrition 80:6-19). The fa/fa Zucker rat exhibits hypercholesterolemia, hyperlipemia, and hyperglycemia and has been used extensively as an animal model for human cardiovascular disease and diabetes. Most of the fatty Zucker rat colonies have been maintained by outbreeding in order to retain heterozygousity at as many loci as possible. However, certain stocks have been inbred to produce animals such as the Zucker diabetic fatty (ZDF) rat which exhibits a more profound diabetic phenotype than the outbred fa/fa Zucker rat (Clark, et al. 1983, Proc. Soc. Exp. Biol. Med. 173: 68-75).
The fa mutation maps to rat chromosome 5 in a region that is syntenic with the db allele on mouse chromosome 4 (Truett, et al. 1991, Proc. Natl. Acad. Sci. 88: 7806-7809). This observation, in conjunction with the similar phenotypes of the fa/fa rat and the db/db mouse, led to the proposal that the fa gene was the rat homologue of the db gene. Higher resolution genetic mapping supports the contention that the fa mutation is located in the gene encoding the rat OB-R (Chua et al. Science 271: 994).
It would be desirable to be able to further experiment with the rodent model system for obesity, and to be able to clone and produce purified rat ob receptor to use in assays for the identification of ligands which may be useful in understanding obesity and for its prevention and treatment.